Lung-Derived Microscaffolds Facilitate Diabetes Reversal after Mouse and Human Intraperitoneal Islet Transplantation

Abstract

There is a need to develop three-dimensional structures that mimic the natural islet tissue microenvironment. Endocrine micro-pancreata (EMPs) made up of acellular organ-derived micro-scaffolds seeded with human islets have been shown to express high levels of key beta-cell specific genes and secrete quantities of insulin per cell similar to freshly isolated human islets in a glucose-regulated manner for more than three months in vitro. The aim of this study was to investigate the capacity of EMPs to restore euglycemia in vivo after transplantation of mouse or human islets in chemically diabetic mice. We proposed that the organ-derived EMPs would restore the extracellular components of the islet microenvironment, generating favorable conditions for islet function and survival. EMPs seeded with 500 mouse islets were implanted intraperitoneally into streptozotocin-induced diabetic mice and reverted diabetes in 67% of mice compared to 13% of controls (p = 0.018, n = 9 per group). Histological analysis of the explanted grafts 60 days post-transplantation stained positive for insulin and exhibited increased vascular density in a collagen-rich background. EMPs were also seeded with human islets and transplanted into the peritoneal cavity of immune-deficient diabetic mice at 250 islet equivalents (IEQ), 500 IEQ and 1000 IEQ. Escalating islet dose increased rates of normoglycemia (50% of the 500 IEQ group and 75% of the 1000 IEQ group, n = 3 per group). Human c-peptide levels were detected 90 days post-transplantation in a dose-response relationship. Herein, we report reversal of diabetes in mice by intraperitoneal transplantation of human islet seeded on EMPs with a human islet dose as low as 500 IEQ.

A Collagen Based Cryogel Bioscaffold that Generates Oxygen for Islet Transplantation

“…This is supported by our in vitro (MTT, live/dead, and GSIS assays) and in vivo (metabolic analysis) data showing that bioscaffolds made from cryogel alone improved islet function and viability when compared to islets alone. Similar results showing improvement in islet function have been reported using bioscaffolds that have been either coated with ECM components43 or those using ECM derived from lung tissue 44,45. However, to minimize the effect of any ROS produced from our hydrophilic collagen‐based cryogel bioscaffold, we tested different concentrations of CPO and found that 0.25 wt% concentration of CPO produced the most desirable results; these bioscaffolds generated biologically relevant concentrations of oxygen17,27 over 21 d while also producing the lowest amount of ROS compared to bioscaffolds which incorporated higher concentrations of CPO.…”

Fibrin supports subcutaneous neonatal porcine islet transplantation without the need for pre‐vascularization

“…[14][15][16] An ECM substitute such as biocompatible scaffolds and hydrogels can be used as a method of cellular delivery and support islet engraftment, survival, and angiogenesis in the subcutaneous site. [27][28][29][30][31] In particular, the native islet ECM and vasculature are removed during the islet isolation process subsequently impairing islet function and thereby necessitating their replacement immediately post-transplant.…”

Influence of rat bone marrow mesenchymal stem cells to rat Langerhans islets viability during co-cultivation with microst ructured collagen‑containing hydrogel

“…При этом нарушается не только васкуляризация и иннервация островков, но и принципиально меняется сигнальное взаимодействие между островковыми клетками (ОК) и компонентами внеклеточного матрикса (ВКМ) [8][9][10], регулирующее множество аспектов физиологии островков, включая выживаемость, пролиферацию и секрецию инсулина. В качестве альтернативы трансплантации ОК предпринимаются немногочисленные попытки создания тканеинженерной конструкции поджелудочной железы (ТИК ПЖ) [11], состоящей из аллогенных ОЛ и биоактивного резорбируемого матрикса, создающего островкам микроокружение, сходное с нативным ВМК, и обеспечивающего ОЛ необходимые условия для выживаемости и функциональной активности [12][13][14][15].…”